Obesity is a chronic disease that has reached global epidemic proportions with over 1 billion adults being overweight (BMI 25-29.9) or obese (BMI >30). In the U.S.A. alone, the number of adults who are either overweight or obese is estimated to be over 150 million and is still on the rise. Currently marketed therapies (orlistat, sibutramine) have demonstrated sub-optimal efficacy (only 5-10% weight loss when used in combination with diet and exercise plans) and/or poor tolerability profiles. More recently, Sanofi Aventis' CB1 receptor antagonist, rimonabant, was withdrawn from the market due to adverse psychiatric side effects. The success of future obesity treatments will depend on their ability to elicit sustained and robust weight loss with improved safety/tolerability profiles.
Obesity (BMI >30) is the long term consequence of an imbalance between energy intake and energy expenditure (Hill et al., 2000). Further, obesity is associated with decreased life span due to numerous co-morbidities that include coronary artery disease, hypertension, stroke, diabetes, hyperlipidemia, osteoarthritis and some cancers. Adiposity is a hallmark of obesity that results from the excessive deposition of the energy storage molecule triacylglycerol (TAG) in all tissues as well as an increase in overall adipose tissue mass due to increased adipocyte size and number. Increases in intracellular TAG and/or TAG precursors in non-adipocyte cell types, adipocyte invasion of non-adipose tissues, and increase in adipose mass are the causative factors of co-morbidities associated with obesity (Van Herpen et al., 2008). Recent studies suggest that the inhibition of diacylglycerol O-acyltransferase 1 (DGAT-1) may be an effective strategy to treat obesity and obesity associated co-morbidities (Chen et al., 2005; Shi et al., 2004).
DGATs are membrane-bound enzymes that catalyze the terminal step of TAG biosynthesis (Yen et al., 2008). Two enzymes, which catalyze the acylation of diacylglycerol (DAG) to form TAG, have been identified and are designated DGAT-1 and DGAT-2. Importantly, the DGAT-1 and DGAT-2 enzymes have no significant protein sequence homology. In addition to catalyzing the acylation of DAG to form TAG, DGAT-1 has also been shown to catalyze the acylation of monoacylglycerol to form DAG (Yen et al., 2005). DGAT-1 and DGAT-2 null mice have been generated and extensively characterized (Smith et al., 2000; Stone et al., 2004). In detail, DGAT-2 null mice are lipopenic and die soon after birth from reductions in substrates for energy metabolism and from impaired permeability barrier function. In contrast, DGAT-1 mice are fertile and viable with a normal life span and do not become obese when fed a TAG rich diet. DGAT-1 null mice exhibit both reduced postprandial plasma TAG levels and increased energy expenditure, but have normal levels of circulating free fatty acids. Conversely, transgenic mice that over-express DGAT-1 in adipose tissue are predisposed to obesity when fed a TAG rich diet and have elevated levels of circulating free fatty acids (Chen et al., 2002).
In humans, DGAT-1 is highly expressed in several tissue types that are relevant to obesity, such as intestine, liver and adipose (Yen et al., 2008). Further, DGAT-1 is predominantly localized to the lumen of the endoplasmic reticulum (Yamazaki et al., 2005). Thus, there are several sites of action for a DGAT-1 inhibitor that can lead to both a reduction in adiposity and body weight. First, blocking DGAT-1 activity in the intestine or liver will inhibit the export of chylomicron and VLDL particles, respectively, thereby reducing peripheral TAG deposition that originates either from dietary TAG re-esterification or from de novo lipogenesis. Second, blocking DGAT-1 activity in adipose tissue will decrease both adipocyte size and number. In both cases, non-esterified fatty acids will be mobilized for use as an energy source rather than used for storage. DGAT-1 inhibition may also generate a peripheral satiety signal resulting in an anorexigenic effect. The phenotype of the DGAT-1 null mice, coupled with DGAT-1's role in human whole body TAG homeostasis, provides a compelling rationale for the investigation of DGAT-1, as a target for the treatment of obesity. Recently, the in vivo pharmacology of a potent orally bioavailable DGAT-1 inhibitor was disclosed (Zhao et al., 2008). Proof of concept studies in rodent models of obesity with this inhibitor demonstrated target engagement, weight loss and reductions in adiposity. This inhibitor showed high oral bioavailability and high systemic exposure.
High systemic exposure of a DGAT-1 inhibitor can potentially result in undesirable side effects such as reduced lactation in nursing females, reduced sebum production, and exacerbation of myocardial injury during ischemia. In detail, human milk TAGs are a major source of nutrition to the nursing infant and systemic inhibition of DGAT-1 would reduce milk TAG production. Female DGAT-1 null mice are unable to nurse their pups due to reduced lactation. Triglycerides are also a major component of human sebum, which is an important skin lubricant. Systemic inhibition of DGAT-1 would reduce sebum production and may result in skin and hair disorders as observed in DGAT-1 null mice. Finally, the systemic inhibition of DGAT-1 could substantially increase free fatty acid availability and utilization by the heart. During ischemia, the utilization of a less efficient fuel source such as fatty acids rather than glucose may enhance myocardial injury.
One approach to improve the therapeutic index of DGAT-1 inhibitors is to exclusively target DGAT-1 expressed in the enterocyte by restricting drug exposure primarily to enterocytes. DGAT-1 inhibitors with low systemic exposure and good oral bioavailability specifically targeted to enterocytes would avoid safety issues potentially associated with compounds that reach high levels in the systemic circulation.